Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

OMAPATRILAT

NFPA

PRODUCT USE

Antihypertensive. Inhibitor of the enzyme involved in the conversion of angiotensin I to
angiotensin II and neutral endopeptidase inhibitor. Normally given by mouth.

SYNONYMS

C19-H24-N2-O4-S2, "(4S-(4alpha(R*), 7alpha, 10alpha, beta))octahydro-4-[(2-mercapto-1-oxo-
7H-pyrido[2, 1-b](1, 3)thiazepine acid", "(4S-(4alpha(R*), 7alpha, 10alpha,
beta))octahydro-4-[(2-mercapto-1-oxo-7H-pyrido[2, 1-b](1, 3)thiazepine acid", "(4S-
(4alpha(R*), 7alpha, 10alpha, beta))octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-
5-oxo-7h-pyrido[2, 1-b]acid", "(4S-(4alpha(R*), 7alpha, 10alpha, beta))octahydro-4-[(2-
mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7h-pyrido[2, 1-b]acid", BMS-186716-01,
"mercaptoacyl derivative of a bicyclic thiazepinone dipeptide", antihypertensive, "ACE
inhibitor", "angiotensin converting enzyme inhibitor"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

EMERGENCY OVERVIEW

RISK

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Although ingestion is not thought to produce harmful effects, the material may still be damaging to the health of the individual following ingestion, especially where pre-  existing organ (e.g. liver, kidney) damage is evident. Present definitions of harmful or toxic substances are generally based on doses producing mortality (death) rather than those producing morbidity (disease, ill-health). Gastrointestinal tract discomfort may produce nausea and vomiting. In an occupational setting however, ingestion of insignificant quantities is not thought to be cause for concern.  Considered an unlikely route of entry in commercial/industrial environments.  ACE inhibitors are fairly safe and serious overdoses are rare. Overdoses may cause low blood pressure, increased heart rate and reversible kidney failure. Side effects of treatment include itch, rash, taste disturbance, allergy, loss of white blood cells, stomach upset, low blood pressure, increased heart rate, mouth ulcers, "pins and needles" in the hands, cough, wheeze and swollen lymph nodes. Damage to the kidneys and low blood pressure may be severe. Large areas of swelling may occur in the tongue, lips, face, extremities, and throat, which may be life-threatening. An itchy skin rash with redness and blistering may occur. Symptoms of low blood pressure are more likely in people who have been on low salt diets and prolonged treatment with diuretics. ACE inhibitors can cause reduction in urine output, and rarely, death due to kidney failure.  

EYE

  Although the material is not thought to be an irritant, direct contact with the eye may produce transient discomfort characterized by tearing or conjunctival redness (as with windburn).  

SKIN

  The material is not thought to produce adverse health effects or skin irritation following contact (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting.  Contact allergies quickly manifest themselves as contact eczema, more rarely as urticaria or Quincke's edema. The pathogenesis of contact eczema involves a cell-mediated (T lymphocytes) immune reaction of the delayed type. Other allergic skin reactions, e.g. contact urticaria, involve antibody-mediated immune reactions. The significance of the contact allergen is not simply determined by its sensitization potential: the distribution of the substance and the opportunities for contact with it are equally important. A weakly sensitizing substance which is widely distributed can be a more important allergen than one with stronger sensitizing potential with which few individuals come into contact. From a clinical point of view, substances are noteworthy if they produce an allergic test reaction in more than 1% of the persons tested.  

INHALED

  The material is not thought to produce adverse health effects or irritation of the respiratory tract (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting.  Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.  

CHRONIC HEALTH EFFECTS

  Principal routes of exposure are usually by skin contact/absorption and inhalation of generated dust.  ACE inhibitors may aggravate kidney and collagen vascular disorders. They may cause injury and death to the fetus late in pregnancy. There has been low blood pressure of the newborn, kidney failure, underdevelopment of the skull and lungs, insufficient amniotic fluid, and fetal growth retardation and limb contractures. Miscarriage or stillbirth may occur. ACE inhibitors can cause growths in glands, but rarely cause malignant cancer.  Exposure to small quantities may induce hypersensitivity reactions characterized by acute bronchospasm, hives (urticaria), deep dermal wheals (angioneurotic edema), running nose (rhinitis) and blurred vision . Anaphylactic shock and skin rash (non-thrombocytopenic purpura) may occur. An individual may be predisposed to such anti-body mediated reaction if other chemical agents have caused prior sensitization (cross-sensitivity).  The material may accumulate in the human body and progressively causetissue damage.  In chronic studies, conducted for 3-6 months in rats, mice and dogs, the  material produced decreased blood pressure, heart weights and microscopic  changes in certain cells of the kidney. Changes were related to the  expected pharmacological effects of the drug. In addition to these  changes, adverse effects occurred at higher doses, in the liver in dogs  and mice. Erosions were reported in the glandular stomach of rats and dogs  at higher doses. In addition dogs (only) developed skin ulcers,  hyperplasia of the spleen and arthralgia with inflammation of several  internal organs, also at higher doses.  Guinea pigs treated orally with omapatrilat did not develop either active  cutaneous anaphylaxis (ACA), passive cutaneous anaphylaxis (PCA) or active  systemic anaphylaxis (ASA) when challenged by intradermal or intravenous  injection. Guinea pigs treated subcutaneously with the compound developed  ACA reactions after subsequent intradermal challenge, but did not exhibit  PCA or ASA reactions after later challenge.  The material was positive for skin sensitisation when evaluated in the  guinea pig maximisation assay.  The material was not mutagenic in the Ames test, an in vitro CHO HGPRT  mammalian-cell forward gene-mutation study and cytogenetic assay in  primary human lymphocytes. It was also negative in a rat oral bone marrow  micronucleus study.  The material was not teratogenic when evaluated in rats at doses up to  1000 mg/kg and in rabbits at doses up to 5 mg/kg/day. The material  produced severe maternal toxicity at a dose of 25 mg/kg and malformations  were noted in the foetuses of 2 does at the maternally toxic dose.  Fertility was not affected in rats treated with up to 500 mg/kg/day for  2-4 weeks, although adverse effects on weight gain were noted at this  dose. In a prenatal and postnatal development study in rats, daily doses  of 10 mg/kg were tolerated, whereas higher doses resulted in adverse  effects in the dams and off-spring.